Synthesis and antihypertensive activity of 4-(1,2-dihydro-2-oxo-1-pyridyl)-2H-1-benzopyrans and related compounds, new potassium channel activators.
The synthesis and antihypertensive activity of 4-(1,2-dihydro-2-oxo-1-pyridyl)-2H-1-benzopyran-3-ols are described. The unsubstituted pyridone adduct lead compound 7e is highly active, with substituents on the pyridone ring leading to a decrease in activity. Strongly electron-withdrawing substituents at the C-6 position are required for optimal activity. When the 2-pyridone ring is replaced by other heterocycles such as 4-pyridone, pyrimidone, pyridazinone, pyrazinone, and 1,4-butanesultam, the activity is maintained. The removal of the 3-hydroxy function (----17a) does not significantly reduce the activity. The elimination of water from the chromanols leads to the formation of the chromenes, which are among the most potent antihypertensives known. The influence of diverse substituents, in particular heterocyclic C-6 substituents, was investigated in the 4-(2-oxo-1-pyrrolidinyl)chroman-3-ol series. Chromanols esterified at the 3-hydroxy group with short-chain acids, maintain their activity. The epoxidation of the chromene double bond also produces active compounds. The rearrangement of the epoxides 22 produces the 3-keto compounds 23 and the enol derivatives 25. The reduction of the ketone 23a produces cis-chromanol 7ab along with its trans isomer 7e. All compounds were tested for oral antihypertensive activity in spontaneously hypertensive rats with a dose of 1 mg/kg; for selected compounds ED30 values as well as the duration of the antihypertensive effect were determined. 4-(1,2-Dihydro-2-oxo-1-pyridyl)-2,2-dimethyl-2H-1-benzopyran-6- carbonitrile (18a) is under development as a coronary vasodilator and a drug for treating angina pectoris.
Bergmann
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Preclinical Pharmaceutical Research, E. Merck, Darmstadt, West Germany.
Gericke
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D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects*; D051381:Rats; D011918:Rats, Inbred SHR; D013329:Structure-Activity Relationship
D000959:Antihypertensive Agents; D001578:Benzopyrans; D004095:Dihydropyridines; D015221:Potassium Channels; C061050:bimakalim